Silberbauer Leo R, Spurny Benjamin, Handschuh Patricia, Klöbl Manfred, Bednarik Petr, Reiter Birgit, Ritter Vera, Trost Patricia, Konadu Melisande E, Windpassinger Marita, Stimpfl Thomas, Bogner Wolfgang, Lanzenberger Rupert, Spies Marie
Department of Psychiatry and Psychotherapy, Medical University of Vienna, Vienna, Austria.
Department of Biomedical Imaging and Image-guided Therapy, High Field MR Centre, Medical University of Vienna, Vienna, Austria.
Front Psychiatry. 2020 Sep 8;11:549903. doi: 10.3389/fpsyt.2020.549903. eCollection 2020.
Converging evidence suggests that ketamine elicits antidepressant effects enhanced neuroplasticity precipitated by a surge of glutamate and modulation of GABA. Magnetic resonance spectroscopic imaging (MRSI) illustrates changes to cerebral glutamate and GABA immediately following ketamine administration during dissociation. However, few studies assess subacute changes in the first hours following application, when ketamine's antidepressant effects emerge. Moreover, ketamine metabolites implicated in its antidepressant effects develop during this timeframe. Thus, this study aimed to investigate subacute changes in cerebral Glx (glutamate + glutamine), GABA and their ratio in seven brain regions central to depressive pathophysiology and treatment.
Twenty-five healthy subjects underwent two multivoxel MRS scans using a spiral encoded, MEGA-edited LASER-localized 3D-MRSI sequence, at baseline and 2 h following intravenous administration of racemic ketamine (0.8 mg/kg bodyweight over 50 min). Ketamine, norketamine and dehydronorketamine plasma levels were determined at routine intervals during and after infusion. Automated region-of-interest (ROI)-based quantification of mean metabolite concentration was used to assess changes in GABA+/total creatine (tCr), Glx/tCr, and GABA+/Glx ratios in the thalamus, hippocampus, insula, putamen, rostral anterior cingulate cortex (ACC), caudal ACC, and posterior cingulate cortex. Effects of ketamine on neurotransmitter levels and association with ketamine- and metabolite plasma levels were tested with repeated measures analyses of variance (rmANOVA) and correlation analyses, respectively.
For GABA+/tCr rmANOVA revealed a measurement by region interaction effect (p < 0.001) and pairwise comparisons showed a reduction in hippocampal GABA+/tCr after ketamine (p = 0.02). For Glx/tCr and GABA+/Glx neither main effects of measurement nor measurement by region interactions were observed (all p > 0.05). Furthermore, no statistically significant associations between changes in any of the neurotransmitter ratios and plasma levels of ketamine, norketamine, or dehydronorketamine were observed (p > 0.05).
This study provides evidence for decreased hippocampal GABA+/tCr ratio 2 h following ketamine administration. As MRS methodology measures total levels of intra- and extracellular GABA, results might indicate drug induced alterations in GABA turnover. Our study in healthy humans suggests that changes in GABA levels, particularly in the hippocampus, should be further assessed for their relevance to ketamine´s antidepressant effects.
越来越多的证据表明，氯胺酮可引发抗抑郁作用，这是由谷氨酸激增和γ-氨基丁酸（GABA）调节所促成的神经可塑性增强所致。磁共振波谱成像（MRSI）显示，在解离过程中给予氯胺酮后，大脑谷氨酸和GABA会立即发生变化。然而，很少有研究评估给药后头几个小时内的亚急性变化，而氯胺酮的抗抑郁作用正是在这个时间段出现的。此外，与氯胺酮抗抑郁作用相关的代谢产物也是在这个时间段形成的。因此，本研究旨在调查大脑中谷氨酸+谷氨酰胺（Glx）、GABA及其比值在七个对抑郁病理生理学和治疗至关重要的脑区中的亚急性变化。
25名健康受试者在基线时以及静脉注射消旋氯胺酮（0.8mg/kg体重，持续50分钟）后2小时，使用螺旋编码、MEGA编辑的激光定位3D-MRSI序列进行了两次多体素MRS扫描。在输注期间和之后的常规时间点测定氯胺酮、去甲氯胺酮和脱氢去甲氯胺酮的血浆水平。基于自动感兴趣区域（ROI）的平均代谢物浓度定量用于评估丘脑、海马、岛叶、壳核、喙前扣带回皮质（ACC）、尾侧ACC和后扣带回皮质中GABA+/总肌酸（tCr）、Glx/tCr和GABA+/Glx比值的变化。分别用重复测量方差分析（rmANOVA）和相关分析测试氯胺酮对神经递质水平的影响以及与氯胺酮和代谢物血浆水平的关联。
对于GABA+/tCr，rmANOVA显示测量与区域的交互作用效应（p<0.001），两两比较显示氯胺酮给药后海马中GABA+/tCr降低（p = 0.02）。对于Glx/tCr和GABA+/Glx，既未观察到测量的主效应，也未观察到测量与区域的交互作用（所有p>0.05）。此外，未观察到任何神经递质比值的变化与氯胺酮、去甲氯胺酮或脱氢去甲氯胺酮的血浆水平之间存在统计学上的显著关联（p>0.05）。
本研究提供了证据，表明氯胺酮给药后2小时海马中GABA+/tCr比值降低。由于MRS方法测量的是细胞内和细胞外GABA的总水平，结果可能表明药物诱导了GABA周转的改变。我们在健康人类中的研究表明，GABA水平的变化，特别是在海马中的变化，应进一步评估其与氯胺酮抗抑郁作用的相关性。
